Clinical Observation and Cause Analysis of Perioperative Superior Cluneal Neuralgia in Vertebral Augmentation.

BACKGROUND: In our clinical practice, we observed that some osteoporotic vertebral compression fracture patients undergoing vertebral augmentation exhibited pain in the iliac crest region. This pain aligned with the diagnostic criteria for superior cluneal neuralgia (SCN) and affected treatment satisfaction. OBJECTIVE: This study aims to clinically observe patients undergoing vertebral augmentation in a hospital setting and analyze the etiology and risk factors associated with SCN. STUDY DESIGN: Retrospective cohort study. SETTING: Inpatient population of a single center. METHODS: We retrospectively analyzed clinical data from 630 patients who underwent vertebral augmentation in our hospital from March 2022 to March 2023. Fifty-two patients enrolled in the study experienced pain that met the diagnostic criteria for superior cluneal neuralgia during the perioperative period of the vertebral augmentation procedures. Those patients were divided into 2 subgroups according to the conditions involved in the occurrence of SCN: Group A (26 patients) had either no preoperative SCN but developed it postoperatively, or had preoperative SCN that worsened or did not alleviate postoperatively. Group B (26 patients) had preoperative SCN that was relieved postoperatively. Additionally, 52 consecutive patients in March 2022 to March 2023. who did not experience SCN during the perioperative period were selected as the control group (Group C). Variables such as surgical segment, age, height, weight, body mass index, duration of hospitalization, chronic low back pain (CLBP), duration of pain, anesthesia, surgical approach, fracture pattern, preoperative visual analog scale (pre-op VAS) score, intraoperative VAS score, one-day VAS score, one-month VAS score, lumbar sacral angle, and sacral tilt angle were statistically described and analyzed. RESULTS: In our hospital, the incidence of SCN during the perioperative period of vertebral augmentation procedures is 8.25% (52/630). Among all the segments of patients who developed SCN during the perioperative period, the L1 segment had the highest proportion, which was 29.03% and 35.14% in Groups A and B, respectively. Group B and Group C showed significant differences in duration of hospitalization (P = 0.012), pre-op VAS scores (P = 0.026), and CLBP (P < 0.001). Group A had significantly higher VAS scores preoperatively (P = 0.026) and intraoperatively (P = 0.004) and in CLBP (P = 0.001) than did Group C. LIMITATIONS: This is a retrospective study. Single-center noncontrolled studies may introduce selection bias. The small sample size in each group might have also led to bias. CONCLUSION: Perioperative SCN associated with vertebral augmentation is significantly correlated with preoperative VAS scores and CLBP. In addition, intraoperative VAS scores might be a factor contributing to the nonalleviation or exacerbation of postoperative SCN.

A deep inverse convolutional neural network-based semantic classification method for land cover remote sensing images.

The imbalance of land cover categories is a common problem. Some categories appear less frequently in the image, while others may occupy the vast majority of the proportion. This imbalance can lead the classifier to tend to predict categories with higher frequency of occurrence, while the recognition effect on minority categories is poor. In view of the difficulty of land cover remote sensing image multi-target semantic classification, a semantic classification method of land cover remote sensing image based on depth deconvolution neural network is proposed. In this method, the land cover remote sensing image semantic segmentation algorithm based on depth deconvolution neural network is used to segment the land cover remote sensing image with multi-target semantic segmentation; Four semantic features of color, texture, shape and size in land cover remote sensing image are extracted by using the semantic feature extraction method of remote sensing image based on improved sequential clustering algorithm; The classification and recognition method of remote sensing image semantic features based on random forest algorithm is adopted to classify and identify four semantic feature types of land cover remote sensing image, and realize the semantic classification of land cover remote sensing image. The experimental results show that after this method classifies the multi-target semantic types of land cover remote sensing images, the average values of Dice similarity coefficient and Hausdorff distance are 0.9877 and 0.9911 respectively, which can accurately classify the multi-target semantic types of land cover remote sensing images.

Genetic control of DNA methylation is largely shared across European and East Asian populations.

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Precision prognostics for cardiovascular disease in Type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with Type 2 diabetes (T2D). METHODS: We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. RESULTS: Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. CONCLUSIONS: Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

People living with type 2 diabetes (T2D) are more likely to develop problems with their heart or blood circulation, known as cardiovascular disease (CVD), than people who do not have T2D. However, it can be difficult to predict which people with T2D are most likely to develop CVD. This is because current approaches, such as blood tests, do not identify all people with T2D who are at an increased risk of CVD. In this study we reviewed published papers that investigated the differences between people with T2D who experienced CVD compared to those who did not. We found some indicators that could potentially be used to determine which people with T2D are most likely to develop CVD. More studies are needed to determine how useful these are. However, they could potentially be used to enable clinicians to provide targeted advice and treatment to those people with T2D at most risk of developing CVD.

Exploring the relationship between adverse working environments and poor psychological states of Chinese workers: A comprehensive study.

BACKGROUND: Employee mental health is linked with job satisfaction and productivity. However, there is a notable lack of empirical evidence regarding the adverse effects of Hazardous Work Environments (HWE) on employee mental health, indicating a significant gap in occupational health research. METHODS: Data from the China Family Panel Studies involving 9972 participants were utilized. Mental health was assessed using the Kessler 6 Psychological Distress Scale at baseline and the 8-item Center for Epidemiologic Studies Depression scale at follow-up. Associations between HWE exposure and mental health were explored cross-sectionally at baseline plus mediation analyses for the influence of sleep duration. Cox proportional hazards regression was used to assess the longitudinal implications of HWE exposure. FINDINGS: Participants exposed to HWE showed a higher risk of having serious psychological distress (OR (95%CI): 1.47 (1.29-1.69)) cross-sectionally at baseline, and this risk rose with increased number of HWE elements (1.30 (1.11-1.52) and 2.18 (1.75-2.72) for 1-2 and ≥ 3 elements, respectively). Longitudinally, HWE exposure was associated with an increased risk of depression (HR (95%CI): 1.10 (1.07-1.14)). Similarly, this risk risen with increased number of HWE elements (1.08 (1.06-1.09) and 1.20 (1.05-1.38) for 1-2 and ≥ 3 elements, respectively) and longer duration of exposure (1.01 (1.00-1.01)). Short sleep duration emerged as a significant mediator between HWE exposure and psychological distress. INTERPRETATION: This study illuminates a robust association between HWE exposure and psychological distress, especially under prolonged and multiple exposures. We advocate for rigorous mental health monitoring and interventions for workers in adverse working environments. FUNDING: CSTB2023NSCQ-BHX0042 and cffkyqdj.

Association Between Circulating Zinc Levels and Risk Factors of Metabolic Syndrome: Insights from a Bi-directional Mendelian Randomization Analysis and Cross-Sectional Study.

Previous studies on the relationship between zinc and metabolic syndrome (MetS) have yielded inconsistent results. This comprehensive study aimed to elaborately explore the impact of zinc on MetS risk factors. The bi-directional Mendelian randomization (MR) analyses were performed to estimate the causal relationship between zinc and MetS risk factors. Additionally, a retrospective cross-sectional study incorporated 4389 subjects to provide a broader perspective in conjunction with the MR analyses. In the MR analyses, genetically instrumented zinc was positively associated with five of the MetS components in Europeans, including BMI, FBG, HbA1c, TC, and LDL-c (ß (95%CI) = 0.023 (0.019-0.027), 0.019 (0.013-0.025), 0.041 (0.022-0.060), 0.027 (0.013-0.042), and 0.018 (0.010-0.026), respectively). In the cross-sectional study, higher concentration of zinc was strongly associated with increased BMI, LDL-c, and UA (ß (95%CI) = 0.040 (0.010-0.085), 0.026 (0.018-0.035), and 1.529 (0.614-2.445), respectively). Moreover, these unfavorable associations were more obvious in women compared to men, with a borderline significant interaction effect for BMI (P=0.051). Our study showed that higher blood concentration of zinc, an essential trace element, was associated with unfavorable changes of the component metabolic risk factors of MetS, especially with BMI and LDL-c. Notably, these associations seemed to be more pronounced in women rather than in men. Further studies are warranted to elucidate the role of zinc status in the underlying mechanisms of MetS.

Precision Prognostics for Cardiovascular Disease in Type 2 Diabetes: A Systematic Review and Meta-analysis.

Background Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with type 2 diabetes (T2D). Methods We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. Results Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. Conclusions Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

Bone marrow microenvironment: roles and therapeutic implications in obesity-associated cancer.

Obesity is increasing globally and has been closely linked to the initiation and progression of multiple human cancers. These relationships, to a large degree, are mediated through obesity-driven disruption of physiological homeostasis characterized by local and systemic endocrinologic, inflammatory, and metabolic changes. Bone marrow microenvironment (BMME), which evolves during obesity, has been implicated in multiple types of cancer. Growing evidence shows that physiological dysfunction of BMME with altered cellular composition, stromal and immune cell function, and energy metabolism, as well as inflammation and hypoxia, in the context of obesity contributes to cancer initiation and progression. Nonetheless, the mechanisms underlying the obesity-BMME-cancer axis remain elusive. In this review, we discuss the recent advances in understanding the evolution of BMME during obesity, its contributions to cancer initiation and progression, and the implications for cancer therapy.

Impaired antibody responses were observed in patients with type 2 diabetes mellitus after receiving the inactivated COVID-19 vaccines.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have been reported to be more susceptible to 2019 novel coronavirus (2019-nCoV) and more likely to develop severe pneumonia. However, the safety and immunological responses of T2DM patients after receiving the inactivated vaccines are not quite definite. Therefore, we aimed to explore the safety, antibody responses, and B-cell immunity of T2DM patients who were vaccinated with inactivated coronavirus disease 2019 (COVID-19) vaccines. METHODS: Eighty-nine patients with T2DM and 100 healthy controls (HCs) were enrolled, all of whom had received two doses of full-course inactivated vaccines. At 21-105 days after full-course vaccines: first, the safety of the vaccines was assessed by questionnaires; second, the titers of anti-receptor binding domain IgG (anti-RBD-IgG) and neutralizing antibodies (NAbs) were measured; third, we detected the frequency of RBD-specific memory B cells (RBD-specific MBCs) to explore the cellular immunity of T2DM patients. RESULTS: The overall incidence of adverse events was similar between T2DM patients and HCs, and no serious adverse events were recorded in either group. Compared with HCs, significantly lower titers of anti-RBD-IgG (p = 0.004) and NAbs (p = 0.013) were observed in T2DM patients. Moreover, the frequency of RBD-specific MBCs was lower in T2DM patients than in HCs (p = 0.027). Among the 89 T2DM patients, individuals with lower body mass index (BMI) had higher antibody titers (anti-RBD-IgG: p = 0.009; NAbs: p = 0.084). Furthermore, we found that sex, BMI, and days after vaccination were correlated with antibody titers. CONCLUSIONS: Inactivated COVID-19 vaccines were safe in patients with T2DM, but the antibody responses and memory B-cell responses were significantly decreased compared to HCs. TRIAL REGISTRATION NUMBER AND DATE: NCT05043246. September 14, 2021. (Clinical Trials.gov).

Altering Ligand Microenvironment of Atomically Dispersed CrN4 by Axial Ligand Sulfur for Enhanced Oxygen Reduction Reaction in Alkaline and Acidic Medium.

Because of the instability and Fenton reactivity of non-precious metal nitrogen-carbon based catalyst when processing the oxygen reduction reaction (ORR), seeking for electrocatalysts with highly efficient performance becomes very highly desired to speed up the commercialization of fuel cell. Herein, chromium (Cr)-N4  electrocatalyst containing extraterrestrial S formed axial S1 -Cr1 N4  bonds (S1 Cr1 N4 C) is achieved via an assembly polymerization and confined pyrolysis strategy. Benefiting from the adjusting  coordination configuration and electronic structure of the metal center through axial coordination, S1 Cr1 N4 C exhibits enhanced the intrinsic activity (half-wave potential (E1/2 ) is 0.90 V versus reversable hydrogen electrode, RHE) compared with that of CrN4 C and Pt/C catalysts. More notably, the catalyst is almost inert in catalyzing the Fenton reaction, and thus shows the high stability. Density functional theory (DFT) results further reveal that the existence of axial S atoms in S1 Cr1 N4 C moiety has the better ORR activity than Cr1 N4 C moieties. The axial S ligand in S1 Cr1 N4 C moiety can break the electron localization around the planar Cr1 N4  active center, which facilitated the rate-limiting reductive release of OH* and accelerated overall ORR process. The present work opens up a new avenue to modulate the axial ligand type of the single-atoms (SAs) active center to enhance intrinsic SAs performances.

Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.

BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life. METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction. RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (ß=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels. CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.

Household air pollution and childhood stunting in China: A prospective cohort study.

Background: Exposure to air pollution, especially indoor air pollution, was associated with an increased risk of childhood stunting. However, few longitudinal studies have explored the long-term impacts of indoor air pollution from household solid fuel use on child growth. We aimed to investigate the association between household air pollution (HAP) from solid fuel use and childhood stunting in Chinese children. Method: The longitudinal data from the Chinese Family Panel Study over 2010-2018 were included in this study with a total of 6,013 children aged 0-15 years enrolled at baseline. Exposure to HAP was measured as solid fuel use for cooking, while solid fuel was defined as coal and firewood/straw according to the questionnaire survey. Stunting was defined as-2SD below the height-for-age z-score (HAZ) of the reference children. Logistic regression and Cox proportional hazards models with time-varying exposures were employed to estimate the association between childhood stunting and HAP exposure. Results: At baseline, children with exposure to HAP from combusting solid fuels had a relatively higher risk of stunting [OR (95%CI): 1.42 (1.24-1.63)]. Among children without stunning at baseline, those living in households with solid fuel use had a higher stunting risk over an 8-year follow-up [HR (95%CI): 2.05 (1.64-2.57)]. The risk of childhood stunting was increased for those with HAP exposure from firewood/straw combustion or with longer exposure duration [HR (95%CI): 2.21 (1.74-2.79) and 3.01 (2.23-4.08), respectively]. Meanwhile, this risk was significantly decreased among children from households switching from solid fuels to clean fuels [HR (95%CI): 0.53 (0.39-0.70)]. Solid fuel use was suggested to be a mediator of the relationship between poor socioeconomic factors (i.e., household income and parental education level) and childhood stunning, with a mediation effect ranging from 11.25 to 14.26%. Conclusions: HAP exposure from solid fuel use was associated with childhood stunting. Poor parental education and low household income might be socioeconomic factors contributing to solid fuel use. Therefore, household energy policies to facilitate access to clean fuels are urgently needed, especially for low-income and low-educated households.

Vitamin D Levels During Pregnancy Are Associated With Offspring Telomere Length: A Longitudinal Mother-Child Study.

CONTEXT: Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased risk for many diseases and adverse later life outcomes. OBJECTIVE: This study investigates the relationship between vitamin D levels and offspring LTL at early life. METHODS: This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96 ±â€…0.44 (mean ±â€…SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography-mass spectrometry. RESULTS: LTL at follow-up was significantly shorter in boys compared with girls (P < 0.001) at age 7. Childhood LTL was negatively associated with childhood BMI (ß ±â€…SE = -0.016 ±â€…0.007)(P = 0.02) and HOMA-IR (ß ±â€…SE = -0.065 ±â€…0.021)(P = 0.002). Multiple linear regression was used to evaluate the relationship between 25(OH)D and LTL, with covariate adjustments. Childhood LTL was positively correlated with total maternal 25(OH)D (0.048 ±â€…0.017) (P = 0.004) and maternal 3-epi-25(OH)D3 (0.05 ±â€…0.017) (P = 0.003), even after adjustment for covariates. A similar association was also noted for cord 3-epi-25(OH)D3 (0.037 ±â€…0.018) (P = 0.035) after adjustment for offspring sex and age. CONCLUSION: Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging.

The Relationships among Plasma Fetuin-B, Thyroid Autoimmunity, and Fertilization Rate In Vitro Fertilization and Embryo Transfer.

Objective: The objective of the study is to investigate the relationships between fetuin-B, thyroid autoimmunity (TAI), and pregnancy outcomes in women undergoing in vitro fertilization and embryo transfer (IVF-ET). Design, Patients, and Measurements. In this prospective study, 180 women who were preparing for pregnancy with IVF-ET were included. There were 120 women with TAI positive and 60 negative controls matched with age and BMI. Results: The 180 women had mean ± SD age of 31.4 ± 4.0 years, with a mean ± SD BMI of 21.0 ± 1.6 kg/m2. There was a significant difference in the level of fetuin-B in women with TAI positive compared with TAI negative group (65.2 ± 18.5 vs. 76.4 ± 25.1, P=0.001). Fetuin-B had a negative relationship with thyroid antibodies even after adjusting for other variables (OR (95%CI) = 0.98 (0.96-0.99), P=0.002). Compared with women with TAI negative, those with TAI positive had a significantly higher risk of low fertilization (20.0% vs. 6.7%; P=0.035). And we found no difference in terms of pregnancy, abortion, implantation, and live birth rate between the two groups. Logistic regression analysis showed that both fetuin-B and TAI were the independent factors to lead the low fertilization of IVF-ET (OR (95%CI) = 0.96 (0.94-0.99) and 4.084 (1.39-15.30), P=0.004 and 0.019, respectively). Conclusion: Fetuin-B was significantly associated with TAI and low fertilization rate in women undergoing IVF-ET. Decreased fetuin-B in women with TAI may be the underlying reason for the lower IVF-ET success rate.

Trefoil factor 3 promotes pancreatic carcinoma progression via WNT pathway activation mediated by enhanced WNT ligand expression.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality with a dismal prognosis that has changed little over the past few decades. Further understanding of the molecular pathology of PDAC progression is urgently required in order to improve the prognosis of patients with PDAC. Herein, it was observed that trefoil factor 3 (TFF3) expression was elevated in PDAC, and was positively correlated with a worse overall patient survival outcome. Forced expression of TFF3 promoted oncogenic functions of PDAC cells in vitro including cell proliferation, survival, foci formation, cancer stem cell-like behavior and invasion, ex vivo colony growth in 3D-Matrigel, and xenograft growth in vivo. Depletion or pharmacological inhibition of TFF3 inhibited these same processes. RNA-Seq analysis and subsequent mechanistic analyses demonstrated that TFF3 increased the expression of various WNT ligands to mediate WNT pathway activation required for TFF3-stimulated PDAC progression. Combined pharmacological inhibition of TFF3 and WNT signaling significantly attenuated PDAC xenograft growth and potentiated the therapeutic efficacy of gemcitabine in both ex vivo and in vivo models. Hence, a mechanistic basis for combined inhibition of pathways enhancing PDAC progression is provided and suggests that inhibition of TFF3 may assist to ameliorate outcomes in PDAC.

Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. METHODS: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). RESULTS: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10-3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. CONCLUSIONS: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings.

Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis.

OBJECTIVE: Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS: The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06-1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (ß = -0.05 [-0.06 to -0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35-2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12-1.70). CONCLUSIONS: Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.

Relative leucocyte telomere length is associated with incident end-stage kidney disease and rapid decline of kidney function in type 2 diabetes: analysis from the Hong Kong Diabetes Register.

AIMS/HYPOTHESIS: Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. METHODS: We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. RESULTS: In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p < 0.001) than the non-progressors (n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p < 0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p < 0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], p = 0.024). CONCLUSIONS/INTERPRETATION: rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.

The Impact of Collaborative Learning and Personality on Satisfaction in Innovative Teaching Context.

Flipped teaching is one of the most popular innovative teaching methods which has attracted a lot of attention and lead to amount of discussion in recent years. Many educators have generally encountered same doubt when implementing flipped education: Is this kind of teaching mode only applicable to students with high learning achievements? In addition, collaborative learning is often applied in flip teaching and it is also an issue worth to explore. In this study, both quantitative and qualitative studies were conducted to examine the potential factors in affecting the learners' satisfaction in flipped education. The survey results from 171 participants showed that collaborative learning and need for cognition are significant predictors of learning satisfaction. In addition, a deeper look at the collaborative learning process was further examined by conducting deep interview. A total of 12 students from 6 different flipped-teaching courses participated the interview. The findings suggested that arranging some activities to encourage students to know each other before class that helps students find corresponding group and facilitates their expertise for collaborative learning. The mechanism significantly influenced team members' engagement, discussion atmosphere, and efficiency. In addition, when learning tasks diversity, it will also enhance students' innovative ability, empathy, and even promote mutual learning.